Project Summary Despite its public health impact and a century of biological research, the pathophysiology of Schizophrenia (SZ) remains poorly understood. One major barrier is the lack of validated and biologically relevant in vivo measures reflecting SZ progression. Accumulating evidence suggests that a central ?immuno-oxidative? pathway involving redox dysregulation, oxidative stress, and NMDA receptor hypofunction, may play a key role in the emergence of neuronal dysfunction and information processing abnormalities characteristic of the disorder. The redox state, reflected by the balance between oxidized NAD+ and reduced NADH, is a key parameter in biological systems indicating the system's ability to carry out energy production; the redox ratio (RR=NAD+/NADH) is thus intimately linked to ATP synthesis processes. The RR is particularly important in the human brain, our most metabolically active organ whose fragile balance of oxidation-reduction is easily disrupted. During intensive energy metabolism, toxic reactive oxygen species are formed; these are eliminated by the antioxidant glutathione (GSH), a critical molecule in resisting oxidative stress. In addition, strong bidirectional influences exist between redox balance and energy metabolism on the one hand and glutamatergic transmission and NMDA receptor function on the other. Thus, the widely-reported abnormalities in glutamatergic function in SZ may be related to abnormal redox balance and bioenergetics. In this proposal, we implement recently developed Magnetic Resonance Spectroscopy (MRS) techniques to measure RR, GSH, and glutamate/glutamine levels in the same brain regions in the same scan, providing convergent evidence on redox dysregulation and glutamatergic function simultaneously in SZ. The current literature suggests that these abnormalities are critical in the early phases of SZ but it is not known how they evolve and influence one another over time. To address this key issue, we will recruit a cohort of individuals at clinical high risk (CHR) and another experiencing a first episode (FE) of psychosis and follow both groups over a 2- year period. Because rate of conversion to frank psychosis is low in CHR groups, we will examine community outcomes in this group as well as conversion. We will also compare findings in this group with those from FE where all individuals have developed frank psychosis. This will allow us to observe unfolding abnormalities at critical stages of the emergence of SZ. We aim to outline the trajectories of biological development in early phases of psychotic disorders and to identify a sensitive predictor for the prodrome and transition to psychosis. The identification of a biomarker associated with CHR which could predict subsequent dysfunction would be a major boost to the development of early intervention and prevention strategies as well as to measuring the impact of early intervention. This proposal uses innovative MRS approaches to ask mechanistic questions using a longitudinal study design. It is likely to be of high impact because it focuses on active disease processes in the critical early stage of SZ.